The role of the LHPA axis in Schizophrenia, Bipolar Disorder and Major Depression
Brian Koehler PhD
There is increasing evidence that the common neuropathology shared by the schizophrenias, bipolar disorders and major depressive disorders may be mediated through the LHPA (limbic-hypothalamic-pituitary-adrenal axis).
Cousins and Young (2005-”Is the hypothalamic-pituitary-adrenal axis at last paying dividends?” in “Bipolar Disorder: The Upswing in Research and Treatment” edited by C. McDonald et al for Taylor & Francis) described the LHPA (limbic-hypothalamic-pituitary-adrenal axis) as follows:
“The structural and functional organization of the HPA axis is well established...In response to stress, neurosecretory cells in the paraventricular nucleus of the hypothalamus secrete corticotrophin releasing hormone (CRH) into the microportal circulatory system of the pituitary stalk. CRH acts on the anterior pituitary, which in turn releases adrenocorticotropic hormone (ACTH) into the systemic circulation. ACTH governs the release of cortisol from the adrenal cortex. Cortisol is the end product of the HPA axis and has numerous central and peripheral effects, including completion of a feedback loop. The HPA axis is highly regulated by this feedback, and by neuronal inputs to the hypothalamus from a number of brain regions (amygdala, hippocampus and certain midbrain nuclei). It is through these neuronal inputs that the system responds to both physical and psychological stressors.
At a cellular level, the effects of cortisol are mediated through intracellular glucocorticoid receptors, of which there are two subtypes: mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). Activated receptors move from the cytosol to the nucleus and interact with transcription factors or bind to specific DNA, thus promoting the expression of various genes. GRs are ubiquitously distributed throughout the body and brain, MRs less so, being found in the kidney and the limbic system. The relative contribution of the receptor subtypes in the regulation of the HPA axis remains unclear. MRs have a high affinity for cortisol and aldosterone: GRs have low affinity for cortisol but avidly bind synthetic steroids. It is proposed that MRs regulate basal cortisol secretion when hormonal levels are low, and that GRs become increasingly important as levels rise and the MRs become saturated. GRs may therefore be pivotal in the response to circadian rhythms and to stress.
The HPA axis is vulnerable in a way that mirrors our understanding of patients’ vulnerabilities. There are genetic effects: genes control the system at various different levels including hormone production and receptor expression. The potential interaction from multiple genes of small effect is large and may predispose to, and perpetuate, abnormal stress reactions. There are early environmental effects: it is well established that the HPA axis is open to influence by early life events in utero and the postnatal period. There are precipitating factors: both physical and psychological stress results in increased production of cortisol. This is useful in times of acute stress but is maladaptive in the long term at cellular and systems levels. There are maintaining factors: serotonergic and dopaminergic neurotransmitter systems are thought to be modulated by cortisol, and ongoing hypercortisolemia may have a detrimental effect upon neuronal function” (pp.116-117).
Dysfunction at all levels of the LHPA axis has been demonstrated in affective disorders, including: enlarged pituitary and adrenal glands; increased cortisol levels and an exaggerated cortisol response to ACTH; and excessive secretion of CRH. These abnormalities are suggestive of an impaired feedback loop, possibly the result of decreased GR receptor number and/or function. Cousins and Young (2005) noted that recently it has been demonstrated that the frontal lobes are adversely affected by cortisol and suffer a pattern of degeneration similar to that observed in the hippocampus. These authors propose that the neurodegenerative effects of cortisol may underlie some of the cognitive deficits observed in patients with severe affective disorders.
Based on the above research observations, novel psychopharmacological strategies are attracting increasing attention, particularly such GR antagonists as mifepristone (Mifeprex, RU-486). Ingestion of GR antagonists is thought to result in an immediate antiglucocorticoid effect followed by a compensatory upregulation of GR numbers. The latter could lead to improved negative feedback, thereby effectively recalibrating the LHPA axis. Research has shown that GR antagonists have been efficacious in severe depression and in animal studies have resulted in increases in receptor number. Cousins and Young (2005), using a randomized, double-blind, placebo-controlled trial, studied the effects of mifepristone as a treatment for bipolar disorder. Results showed significant improvement in neurocognitive functioning and levels of depression as well. They argued that hypercortisolemia is associated with neurocognitive impairment and neurodegeneration and that the disruption in mood and cognition observed in bipolar disorder, could arise, partially, from LHPA axis dysfunction.
Riva (2005) (”The role of neurotrophic factors in the stress response” published in “Handbook of Stress and the Brain: Part 1 The Neurobiology of Stress” edited by T. Steckler, N. H. Kalin and J. M. H. Reul in 2005 for Elsevier) noted:
“...excessive glucocorticoids are deleterious for neuronal cells and may play a relevant role in several psychiatric disorders, such as depression, schizophrenia, and posttraumatic stress disorder (PTSD), which are characterized by complex changes in brain plasticity...it has been well documented that stress during prenatal and early postnatal development may leave permanent traces on brain function determining changes in the activity of the HPA axis and interfering with the process of neuronal maturation...prolonged exposure to stress can alter brain activity and function through changes, which usually lead to reduced cellular plasticity and enhanced neuronal vulnerability...indeed structural alteration and reduced neurogenesis in selected brain regions have been reported to occur following prolonged stress exposure” (pp.665-666).
Neuronal size is known to correlate with the extent of a neuron’s efferent and afferent connections, and therefore reduced neuronal size suggests functional and/or structural dysconnectivity (Cotter 2005- “Stress on the brain: neuropathology and cortisol dysregulation in bipolar disorder” in “Bipolar Disorder: The Upswing in Research and Treatment” edited by C. McDonald et al for Taylor & Francis ). In major depressive disorder (MDD) and bipolar disorder (BPD) there is evidence for reduced neuronal size in the anterior cingulate cortex, the dorsolateral prefrontal cortex and the orbitofrontal cortex. There may also be a reduced density of larger neurons in both of these conditions. In bipolar disorder, reduced density of smaller interneurons have been described. Deficits in glial cell number and density have also been observed in these disorders-in the orbitofrontal cortex, anterior cingulate cortex and dorsolateral prefrontal cortex. Glial cells, which are composed of three types of cells, microglia, oligodendroglia and astrocytes, have traditionally been thought of as serving supportive functions for neurons-so called “mind-glue”- but now we know that they have primary roles in glutamatergic neurotransmission, glucose metabolism and neurotrophic support. Synaptic changes have also been observed in MDD and BPD. three synaptic proteins (synaptophysin, complexin I and growth-associated protein-43-GAP-43, have been shown to be reduced in the anterior cingulate cortex in BPD, with only complexin II reduced in MDD. In the hippocampus, reduced levels of synaptic associated protein-25 and complexin I and II have been observed in BPD. and not in MDD. Synaptic pathology is present in mood disorders with more marked changes seen in BPD than MDD. Subcortical white matter hyperintensities (WMI) have been observed in BPD and MDD, usually around the basal ganglia and in the periventricular region. Cotter (2005) noted that WMH reflect damage to white matter tracts, suggesting that the mood disorder is due to interference in the frontal cortical-subcortical connections.
Cotter (2005) suggested that there are significant similarities in the neuropathology of MDD, BPD and schizophrenia. Macroscopic neuroanatomical investigations of neural pathology in schizophrenia, BPD and MDD reveal differences that are generally quantitative rather than qualitative in nature, ventricular dilatation and reduced hippocampal and frontal brain volumes are seen in schizophrenia, but they are also present to a lesser degree in MDD and BPD. At a microscopic level, reductions in dendritic spine density, neuronal size, and synaptic proteins have been observed in both mood disorders and schizophrenia. Glial cell deficits may also be a feature of all three conditions-schizophrenia, BPD and MDD. According to Cotter, this similar pattern of changes in cortical cellular architecture in schizophrenia and mood disorders suggests a common neuropathophysiological process which may underlie aspects of these psychiatric conditions. Cotter believes that glucocorticoid-related neurotoxicity is a good candidate underlying the above noted changes across these various psychiatric disorders. Recently, reduced GR gene expression has been observed in the frontal cortex in persons diagnosed with schizophrenia and MDD. High levels of cortisol result in reduced neuronal volume and dendritic arborization, and this has been observed in both disorders. Elevated plasma cortisol levels are associated with hippocampal volume reductions in MDD, PTSD, Cushing’s disease and normal aging, and such reductions have been observed in initial psychotic episodes. The functional effects of glucocorticoids on reducing hippocampal glial cell activation and proliferation mirrors the glial cell deficit seen in MDD, BPD and schizophrenia. Therefore, the glial cell deficit in these disorders may relate to glucocorticoid (cortisol) effects.
There is accumulating evidence that the neural changes occurring during and after first episodes of BPD and schizophrenia, are not neurodevelopmental in the traditional sense. The changes are not specific to schizophrenia. Macroscopically and microscopically, they are also present, to a generally milder degree, in subjects with BPD and MDD, and, importantly, they are congruent with glucocorticoid-related neural changes. Therefore, these brain changes may be epiphenomena secondary to stress-related changes in LHPA glucocorticoid functioning and not “primary pathogenetic pathways” (Cotter 2005, p.127). These changes could have significant clinical effects through diminishing neuronal and cortical functioning, thereby complicating recovery from the primary illness, be it schizophrenia, BPD or MDD. These neural changes could possibly be reversed through therapies that are neuroprotective, e.g., glucocorticoid receptor antagonists, or which act to promote neuroprotective cell-signaling pathways.
Brian Koehler PhD
Postdoctoral Faculty
New York University
80 East 11th Street #339
New York NY 10003
212.533.5687
brian_koehler@psychoanalysis.net
